"Chemo brain" is a term used to describe a host of symptoms associated with chemotherapy treatment in human cancer patients, such as impaired memory, attention, and concentration. It has been suggested that one of the ways chemotherapy drugs may be eliciting cognitive and behavioral effects is through inhibition of neurogenesis, a normally-occurring ongoing generation of new neurons, in the hippocampus, a brain structure shown to be involved in both learning and memory processes and regulation of mood state. In young mice, thousands of cells are produced every day, although many of them do not survive long enough to mature and integrate into the existing network, and this process slows with age. Factors such as physical activity, enriched living environment, learning tasks and antidepressant medications have been shown to enhance neurogenesis. Other factors such as stress and corticosteroid hormones inhibit genesis and survival of these cells, and this has been correlated both with impairments in some types of memory and with onset of depression. Recent work by our group and others have demonstrated impaired memory in mice following treatment with some chemotherapy drugs. These impairments of memory are accompanied by impaired cell proliferation in the dentate gyrus, although a causal relationship impairments has not been conclusively demonstrated. The experiments proposed in this application will continue to address the impact of chemotherapy drugs on various types of memory formation as well as susceptibility to anxiety and depression-related behaviors in mice. Our experimental design includes several drugs that do not cross the blood-brain barrier in order to determine whether the cognitive deficits following chemotherapy are specific to drugs that readily enter the brain, or are due to broader peripherally generated responses that influence brain function. We will also examine effects of these drugs on neurogenesis in the hippocampal dentate gyrus using histological methods to determine the extent to which impairments are correlated. Additionally, we will investigate the effects of chemotherapy in aged mice, in which neurogenesis is minimal, to determine whether chemotherapy may be influencing cognitive function by alternative pathways. This work is relevant to public health given the putative contributions of impaired neurogenesis to cognitive and behavioral deficits, in particular for those patients subjected to chemotherapy for the treatment of cancer, and especially in light of recent promotion of high-dose chemotherapy treatment for aggressive recurrent brain malignancies in young people. PUBLIC HEALTH RELEVANCE: The research in this proposal will investigate cognitive and behavioral deficits resulting from administration of the chemotherapeutic drug thioTEPA in mice, in an effort to understand neurological and cognitive deficiencies experienced by humans subjected to this or other chemotherapeutic drugs for the clinical treatment of cancer. More generally, this research will investigate the potential relationships between hippocampal neurogenesis and both processes of learning and memory and in the development of anxiety or depression-related behaviors.